A phase 1, first-in-human, dose-escalation and biomarker trial of liposomal gemcitabine (FF-10832) in patients with advanced solid tumors.
Authors: Erkut Hasan Borazanci, Filip Janku, Erika P. Hamilton, Jacob Stephen Thomas, Shiraj Sen, Siqing Fu, Catherine A. Wheeler, David S. Wages, Takeshi Matsumoto, Susumu Shimoyama, Naoki Yamada, Ruth Ann Subach, Timothy Madden, Mary Johansen, Gary Maier, Kin Cheung, Ron Korn, Gerald Steven Falchook
Journal: Journal of Clinical Oncology (2022)

3097 Background: FF-10832 is a stable liposomal formulation of gemcitabine (GEM) shown to overcome resistance through increased plasma stability and enhanced tumor drug delivery. Macrophage uptake and immune activation in the tumor microenvironment (TME) play a role in the superior efficacy of FF-10832 compared to GEM, with selective, marrow-sparing biodistribution contributing to an improved safety profile. Methods: A 3+3 design determined the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended Phase 2 dose (RP2D). FF-10832 was administered IV once or twice per cycle on a 28 or 21-day schedule until disease progression or unacceptable toxicity. Circulating immune cell populations were measured over time by flow cytometry. Results: Patients (pts) [n = 73, 26M/47F; median age, 64 (range, 26–84); # prior therapies, 3 (1–11); prior GEM, 60%] received FF-10832 on Day 1 and 15 Q28 days (1.2–30 mg/m 2 ), Day 1 and 8 Q21 days (12–23 mg/m 2 ), or Day 1 only Q28 or 21 days (30–55 mg/m 2 ); median # cycles = 2 (1–14) &amp; time on study = 8.3 (4–60) weeks. Common drug-related adverse events were Grade (Gr) ≤2 rash (22%), nausea (22%, 1 Gr 3), and pyrexia (21%, 2 Gr 3). Dose-limiting Gr ≥3 cellulitis/skin ulcers were observed at ≥23 mg/m 2 with twice per cycle dosing and those regimens discontinued. Dose frequency was reduced to Day 1 only, which was well-tolerated without significant skin toxicity. Gr ≥3 thrombocytopenia and pneumonitis were observed at 55 mg/m 2 Q21 days and the MTD confirmed at 40 (Q21) and 48 mg/m 2 (Q28). Median OS = 25.3 (95%CI: 16–27.1) weeks and PFS = 9.6 (95%CI: 7.9–17.6) weeks. Three of 35 evaluable pts achieved a partial response (PR): one pt with gallbladder cancer who previously progressed on GEM achieved a 50%↓ by Cycle 13 at 40 mg/m 2 Q28 days &amp; maintains response on study at 60 weeks; two pts with pancreatic cancer had ≥30%↓: one adenocarcinoma after 2 cycles at 4.8 mg/m 2 Days 1 &amp; 15 Q28 days, and one acinar cell after 7 cycles at 40 mg/m 2 Q28 days who remains on study. Stable disease (SD) was observed in 16 pts; 9 for ≥20 weeks. AUC increased in proportion to dose without accumulation. An extended plasma t 1/2 (hrs) for released (39) &amp; total GEM (26) with a free fraction &lt; 1% of total GEM concentrations suggests continuous release in the TME. Pts with PR or SD had dose and time-related log decreases in Ki67+ regulatory T cells relative to total CD4+ cells with increases in anti-tumor CD8+ cells, suggesting a shift to a more immunocompetent environment. Conclusions: FF-10832 was well-tolerated in heavily pre-treated pts with solid tumors, with evidence of anti-tumor activity in pts who progressed on prior GEM. Prolonged, continuous exposure and enhancement of anti-tumor immunity may contribute to improved efficacy. Expansion is ongoing in biliary tract cancer pts treated at the RP2D/schedule of 40 mg/m 2 Day 1 of a 21-day cycle. Clinical trial information: NCT03440450.